Eosinophillic lung diseases

EOSINOPHILIC LUNG DISEASES

ANKIT MITTAL

MD 1ST YEAR

(PULMONARY MEDICINE)

DEFINITION

• Heterogenous group of pulmonary disorders

characterized by pulmonary parenchymal or peripheral

blood eosinophilia.

• May involve

1. Parenchyma – eosinophilic pneumonia

2. Airways - ABPA

Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1213

EOSINOPHIL

- Two-lobed, polymorphonuclear leukocyte, 12 to 15 um.

- Stains red with Eosin, a red dye. (granules)

- Granules consists of • Histamines,• Proteins such as eosinophil peroxidase, RNAse,

DNAse, lipase, plasminogen & major basic protein.

Pathological basis of diseases, Robbins & Cotran: 7th edition

EOSINOPHIL- FUNCTIONS

Competing theories:• Host defense• Modulator of inflammation• Tissue destroyer

- Kills Parasites, tumor cells, respiratory epithelial cells.

- Chemotaxis :

Complement, histamine, ECF-A, PAF, LT’s,

lymphokines, tumor factors, IL-5


EOSINOPHILIC ACTIVATION

Th1/Th2 imbalanceIL-4,IL-5, IL-13


WHAT’S NORMAL

• *The normal AEC : <500/mm3 . Mild eosinophilia : 500-1500/mm3 Moderate eosinophilia : 1500-5000/mm3 Severe eosinophilia : > 5000/mm3

**Bronchoscopy (BAL) EOS % & not absolute number• Normal volunteers < 2% • Increased >5%• Primary pulmonary eosinophilic syndromes >20%*Practical approach to the patient with hypereosinophilia: Florence Roufosse, Peter F. Weller :J ALLERGY CLIN IMMUNOL ; JULY 2010

**Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1214

CLASSIFICATION

In 1932, Loeffler: -• Association between pulmonary infiltrates and

eosinophilia

In 1952 Reeder and Goodrich:-

• Pulmonary Infiltrates & Eosinophilia (coined ‘PIE syndrome’)


CLASSIFICATIONCroften et al, 1952 (clinical criteria) * • Simple pulmonary eosinophilia (Loeffler’s)• Prolonged pulmonary eosinophilia • Tropical eosinophilia • Pulmonary eosinophilia with asthma• Polyarteritis nodosa (PAN)

*Crofton JW, Livingstone JL, Oswald NC, et al: Pulmonary eosinophilia. Thorax 1952; 7:1-35 .

DISEASES ASSOCIATED WITH

PULMONARY INFILTERATES

AND

EOSINOPHILIA

Diseases Associated with Pulmonary Infiltrates & Eosinophilia

• Pulmonary Eosinophilic Syndromes of Known Cause

• Pulmonary Eosinophilic Syndromes of Unknown Cause

• Other Lung Diseases Variably Associated with Eosinophilia

Murray & Nadel’s textbook of respiratory medicine , 5 th edition

Pulmonary Eosinophilic Syndromes of Known Cause:

• Parasitic-induced eosinophilic pneumonias (including Loeffler’s syndrome)

• Drug-or toxin-induced eosinophilic pneumonias

• Tropical pulmonary eosinophilia

• Allergic bronchopulmonary mycosis


Pulmonary Eosinophilic Syndromes of Unknown Cause

• Idiopathic acute eosinophilic pneumonia

• Chronic eosinophilic pneumonia

• Churg-Strauss syndrome (allergic granulomatosis and angiitis)

• Idiopathic hypereosinophilic syndrome


Other Lung Diseases Variably Associated with Eosinophilia

• Asthma/allergy

• Bronchocentric granulomatosis

• Bronchiolitis obliterans-organizing pneumonia

• Infections –

– Fungal (Coccidioidomycosis, Aspergillus,P. jirovecii)

– Tuberculosis


Other Lung Diseases Variably Associated with Eosinophilia

• Interstitial lung disease:

- Idiopathic pulmonary fibrosis

- Collagen-vascular disease associated

- Sarcoidosis

- Eosinophilic granuloma (pulmonary histiocytosis X)

• Malignancy:

- Non-small-cell cancer of lung

- Non-Hodgkin’s lymphoma

- Myeloblastic leukemia

Miscellaneous (lung transplantation, ulcerative colitis)Murray & Nadel’s textbook of respiratory medicine , 5 th edition

EOSINOPHILIC PNEUMONIAS WITH ACUTE PRESENTATIONS

• Loeffler’s Syndrome (Simple Pulmonary Eosinophilia)

• Parasitic Infections

• Drug and Toxin-Induced Pulmonary Eosinophilic

Syndromes

• Idiopathic Acute Eosinophilic Pneumonia


Loeffler’s Syndrome:

Simple

Pulmonary Eosinophilia

Loeffler’s Syndrome (Simple Pulmonary Eosinophilia)

• In 1932, Loeffler first described a clinical syndrome characterized by:

- mild respiratory symptoms

- peripheral blood eosinophilia and

- transient, migratory pulmonary infiltrates.

• Affects all ages

• Immune hypersensitivity to Ascaris lumbricoides - likely cause.



• CLINICAL FEATURES Low-grade fever Nonproductive cough Dyspnea (mild to severe) and Hemoptysis(occ.)

• Respiratory manifestations- self-limited

• Typically resolving in 1 to 2 weeks.



INVESTIGATIONS:• Peripheral blood - moderate to extreme eosinophilia

• Sputum - contains eosinophils.

• C X ray- Transient, migratory, nonsegmental interstitial & alveolar infiltrates (often peripheral or pleural based).

• PFT: typically Reveals mild to moderate restrictive ventilatory defect with a reduced DLCO


Radiology

Jeong Y J et al. Radiographics 2007;27:617-637

SPE in a 25-year-old man with 13.5% peripheral eosinophilia.


MICROSCOPY

Drug and Toxin-Induced Pulmonary Eosinophilic Syndromes


• Onset : Acute or subacute.

• Respiratory symptoms: vary widely in severity

- mild Loeffler’s-like illness with dyspnea, cough, and

fever

- severe fulminant respiratory failure.

• P.F.T.: obstructive physiology is not common.



RADIOGRAPHIC FINDINGS:• Not specific• Interstitial or alveolar infiltrates are typical.

CT FINDINGS:• Bilateral consolidation and ground-glass opacities, both

of which are frequently peripherally located.

• A concomitant skin rash and pleural effusion can

support the diagnosis of drug-induced eosinophilic

pneumonia.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1216


PROGNOSIS:• Favorable in most cases.

• Elimination of exposure to the drug/toxin leads to resolution of

- symptoms

- eosinophilia

- pulmonary infiltrates,

- normalization of lung function within a month.

• Corticosteroids is not universally required, but may hasten recovery in ill patients.


Idiopathic

Acute Eosinophilic

Pneumonia

Idiopathic Acute Eosinophilic Pneumonia

• More common in younger men, with a mean age of approximately 30 years

• Occurs commonly in previously healthy persons.

• Also seen in persons with h/o CML, HIV infection, recent

commencement of smoking, involvement in unusual

activities (like cave exploration, plant repotting, indoor

renovations etc.)

*N Engl J Med 321:569–574, 1989.

*Allergy 60:841–857, 2005.


** DIAGNOSTIC CRITERIA:

1. Acute onset of febrile respiratory manifestations (≤1

month duration before consultation)

2. Bilateral diffuse infiltrates on chest radiography

3. Hypoxemia, with PaO2 on room air < 60 mm Hg,

and/or PaO2 /FiO2 <= 300 mm Hg, and/or oxygen

saturation on room air < 90%

• ** Tazelaar HD, Linz LJ, Colby TV, et al: Acute eosinophilic pneumonia: Histopathologic findings in nine patients. Am J Respir Crit Care Med 1997; 155:296-302.

• Pope-Harman AL, Davis WB, Allen ED, et al: Acute eosinophilic pneumonia: A summary of 15 cases and a review of the literature. Medicine (Baltimore) 1996; 75:334-342

• Philit F, Etienne- Mastroianni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: A study of 22 patients. Am J Respir Crit Care Med 2002; 166:1235-1239


** DIAGNOSTIC CRITERIA: (CONTINUED)

4. Lung eosinophilia , with > 25% eosinophils in BAL(or

eosinophilic pneumonia at lung biopsy)

5. Absence of infection, or of other known causes of

eosinophilic lung disease (especially exposure to drug

known to induce pulmonary eosinophilia.

• ** Tazelaar HD, Linz LJ, Colby TV, et al: Acute eosinophilic pneumonia: Histopathologic findings in nine patients. Am J Respir Crit Care Med 1997; 155:296-302.

• Pope-Harman AL, Davis WB, Allen ED, et al: Acute eosinophilic pneumonia: A summary of 15 cases and a review of the literature. Medicine (Baltimore) 1996; 75:334-342

• Philit F, Etienne- Mastroianni B, Parrot A, et al: Idiopathic acute eosinophilic pneumonia: A study of 22 patients. Am J Respir Crit Care Med 2002; 166:1235-1239


CLINICAL FEATURES:• Presents as an acute illness with fever, myalgias, cough,

dyspnea, pleuritic chest pain, & hypoxemia (PaO2 < 60)

• Patients often have diffuse crackles on auscultation & develop overt respiratory failure requiring mechanical ventilation.

• Presents as ARDS but shock & extrapulmonary organ failure characteristically absent

Chest 2008; 133:1174-1180


INVESTIGATIONS:• A moderate leukocytosis is typical, but in contrast to

other forms of AEP, blood eosinophilia is usually absent.

• Serum IgE levels may be moderately elevated.

• Striking eosinophilia (25 to 50 percent) is present in BAL

fluid.

• Pulmonary function tests reveal a restrictive ventilatory

defect with a reduced DLco



RADIOLOGY:• Early in the course of illness, the chest radiograph

reveals subtle, patchy infiltrates with Kerley B lines.

• Diffuse symmetric alveolar and interstitial infiltrates

resembling ARDS with a ground-glass or micronodular

appearance develop within 48 hours.

• Bilateral infiltrates is a defining feature of the disease.

• Small to moderate bilateral pleural effusions is common. Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1217


RADIOLOGY:• CT scanning confirms the presence of: - diffuse parenchymal ground-glass attenuation and

consolidation. - prominence along bronchovascular bundles and septae. - pleural effusion.

• Fluid analysis typically reveals a high pH and marked eosinophilia.


Radiology

•B/L Opacities with mixed alveolar & interstitial opacities

•B/L Pleural effusion & Kerley B lines

•Air space consolidation

•Ground glass haze

•Interlobular septal thickening

•B/L pleural effusion



LIGHT MICROSCOPY:• Prominent eosinophil infiltration in alveolar

spaces, bronchial walls, and, to a lesser

degree, the interstitium.

• The pathological pattern of diffuse alveolar damage with

eosinophilic infiltrates should suggest the possibility of

Acute Eosinophilic Pneumonia.


Microscopy

Eosinophils infiltrating the alveolar spaces & wall with Diffuse alveolar damageJeong Y J et al. Radiographics 2007;27:617-637


• Elevated levels of the fungal cell wall component

β-d-glucan have been described in the BAL fluid of

patients with AEP suggesting a possible association

between exposure to fungus and development of disease.

• Idiopathic AEP is a diagnosis of exclusion and should be

considered in a patient who presents with apparent

acute lung injury (ALI) or ARDS without a typical

antecedent illness.



TREATMENT:• Initial doses of methyl-prednisolone typically

used range from 60 to 125 mg administered

every 6 hours.

• After resolution of respiratory failure, oral

prednisone (in doses of 40 to 60 mg per day) may

be continued for 2 to 4weeks with a subsequent

slow taper over the next several weeks



PROGNOSIS:• Idiopathic AEP carries an excellent prognosis.

• Rapid dramatic responses to corticosteroid therapy with

abatement of fever and respiratory symptoms within

hours and complete resolution of infiltrates usually

within 1 month.



• Absence of clinical relapse is characteristic.

• Follow-up pulmonary function testing is

generally normal, although a small number of

patients may demonstrate mild reductions in

DLco or lung volumes.


CHRONIC EOSINOPHILIC

PNEUMONIA

CHRONIC EOSINOPHILIC PNEUMONIA

• First described by Carrington et al in 1969.

• Peak incidence : 30 to 40 yrs. F>M

• Most cases occur in Caucasians

• 1/3 to ½ h/o: atopy, allergic rhinitis, or nasal polyps.

• 2/3 rd adult-onset asthma: preceding or concurrent with

the occurrence of CEP



CLINICAL FEATURES:• Typically subacute presentation.

• Symptoms present for several months before diagnosis.

• Common presenting complaints include:

- Low-grade fevers,

- Drenching night sweats

- Moderate (10-to 50-pound) weight loss.

- Cough



• Patients ultimately develop progressive dyspnea, which

may be associated with wheezing in those with adult-

onset asthma.

• Less commonly ARDS with severe hypoxemia.

• No major extrapulmonary manifestations.

• Rarely, arthralgia, skin rash, pericarditis, unexplained

heart failure have been described.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1220


• Moderate leukocytosis.

• The majority (66 to 95 percent) have peripheral blood

eosinophilia(> 6≈90%)

• Moderate normochromic,normocytic anemia and

thrombocytosis may be present.

• The ESR is typically elevated (>20mm).



• IgE levels are elevated in up to 50% of cases.

BRONCHOALVEOLAR LAVAGE:

• Increased eosinophils, typically accounting for 40% or

more of the WBC’S.

• Blood and sputum cultures routinely fail to identify an

infectious etiology in these patients.



PULMONARY FUNCTION TEST:• Depends on the stage and severity of the disease.

• In the initial stage prior to treatment with corticosteroids, testing may reveal:

- restrictive, due to acute eosinophilic infiltration of lung parenchyma. - obstructive, common in patients with a history of asthma. - normal physiology.



RADIOGRAPHIC FEATURES:• Peripherally based, progressive dense infiltrates with ill

defined margins.

• Infiltrates are most commonly bilateral, located in the mid

to upper lung zones.

• They are frequently nonsegmental, subsegmental, or

lobar in distribution and apposed to the pleura & may

mimic loculated pleural fluid. Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1220


• The characteristic “photographic negative of pulmonary

edema” appearance (<50% cases) results if extensive

infiltrates surround major portions of or the entire lung.

• Pulmonary infiltrates a/w CEP are typically non-migratory

& affect the outer two-thirds of lung fields

• Rapid resolution of infiltrates occurs following

corticosteroid treatment, with recurrences in identical

locations.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1220


CT SCAN FINDINGS:• Ground-glass opacities without clear consolidation.

• Mediastinal adenopathy

• Less typical features include:- nodular infiltrates- Linear oblique/vertical densities- Areas of fibrosis unassociated with anatomic divisions.



CT SCAN FINDINGS: (contd)• Findings may vary depending on the timing of CT

relative to onset of symptoms.

• Typical areas of dense, peripherally located airspace

consolidation are found in most cases within the first

several weeks of disease onset.

• Streaky band-like opacities may appear when symptoms

have been present for more than 2 months.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1220

Radiology

•B/L Opacities in Upper & Mid Zone

•Photographic negative of pulmonary edema

•B/L Peripheral opacities

•Ground glass haze

•Septal line thickening



HISTOPATHOLOGY:• Varying degree of leukocytic infilterates in alveolar

airspaces & interstitium.

• Predominantly eosinophilic with macrophages,

lymphocytes & occassional plasma cells.

• Focal edema of capillary endothelium, focal type II

epithelial cell hyperplasia, proteinaceous alveolar

exudates & multinucleated histiocytes within alveolar

spaces.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1221


HISTOPATHOLOGY:• Proliferative bronchiolitis obliterans (1/3rd cases)

• Mild, non necrotising microangitis affecting small venules

may be seen.

• Less than 20% may have:- Frank intra-alveolar necrosis- eosinophilic microabcess- Non caseating granuloma.


Microscopy

Eosinophilic infiltration of alveolar walls with variable fibrosis



DIAGNOSIS:• The diagnosis of CEP is based on clinical, radiographic,

& BAL findings, and on the inability to document

pulmonary or systemic infection.

• Transbronchial biopsy, usually performed to rule out

other diagnostic entities.

• In most reported series, open lung biopsy has been

required only rarely to establish the diagnosis.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1221


DIAGNOSIS: (contd)• Because of the rapid and dramatic responsiveness of

CEP to steroid treatment, a therapeutic trial of steroids

is often useful in establishing the diagnosis.

• Failure to document rapid clinicial improvement should

alert the clinician to consider other diagnosis.



DIFFERENTIAL DIAGNOSIS:• Infection (especially TB and fungal diseases like

cryptococcosis).• Sarcoidosis.• Loeffler’s syndrome.• Desquamative interstitial Pneumonitis.• Bronchiolitis Obliterans-Organizing Pneumonia.• Chronic Hypersensitivity Pneumonitis.• Eosinophilic Granuloma.



TREATMENT:• Corticosteroids are the mainstay of therapy for CEP.

• Dramatic clinical, radiographic, and physiological

improvements have been documented following steroid

treatment in all series Reported.

• Even patients presenting with severe respiratory failure

may respond welll to steroids.



• Treatment with steroids leads to:- Defervescence within 6 hours- Reduced dyspnea, cough, and blood eosinophilia

within 24 to 48 hours- Resolution of hypoxia in 2 to 3 days- Radiographic improvement within 1 to 2 weeks- Complete resolution of symptoms within 2-3 weeks- Normalization of the chest radiograph within 2

months.



STEROID REGIMEN:• No comparative study for appropriate dose or duration.

• Recommended regimen: prednisone(40-60 mg/day) until

2 wks after resolution of symptoms & Xray abnormalities.

• The dose of prednisone can then be tapered slowly.

• Treatment is usually maintained for at least 3 months &

optimally for 6 to 9 monthsFishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1222


PROGNOSIS:• Generally favourable

• Patients may require 1 to 3 years of initial steroid

treatment for disease control & up to 25% may require

long-term maintenance treatment (2.5-10mg/day)

• Some patients may respond to inhaled corticosteroids allowing discontinuation of oral steroids.



PROGNOSIS: (contd)• Relapse occurs in approximately one-third to one-half of

patients when steroids are tapered or discontinued.

• No obvious factors exist to identify persons who are likely to relapse or require long-term steroids.

• Relapses are more common in persons treated initially with a short course (less than 6 months) of steroids


CHURG-STRAUSS SYNDROME

(ALLERGIC GRANULOMATOSIS

AND ANGIITIS)


• In 1939, Rackemann & Greene: reported a subgroup of

patients with P.A.N. & concomitant allergic disease.

• In 1951, Churg and Strauss: first described the histopathology and clinical features.

• They Reported a form of necrotizing vasculitis in several

organs, associated with eosinophilic tissue inflammation

& extravascular granulomas, occurring in asthmatics,

with associated fever and peripheral hypereosinophilia.

Ann Intern Med 143:632–638, 2005Arthritis Rheum 52:2926–2935, 2005


• CSS is an uncommon systemic disease & typically

affects multiple-organ systems.

• 10% of all patients with vasculitis prove to have CSS.

• Increased incidence is seen in asthmatics.

• Precise incidence is unknown due to uncertainities

regarding the diagnosis & variable clinical presentation.



• Occur in patients of any age most commonly between 38

to 50yrs.

• No clear gender predominance.

• Among women, disease onset has been reported during

pregnancy.


Criteria for diagnosis of CSS


• Subacute course (with symptoms ranging over months to

years)

• Three distinct clinical phases of the disease have been

recognized:

1) The prodromal phase,

2) The eosinophilic phase,

3) Vasculitic phase .



1. PRODROMAL PHASE: • Late-onset (in the second or third decade) allergic rhinitis

and atopy in persons often lacking a family history of

atopy.

• Severe allergic rhinitis, sinusitis, drug sensitivity, and

asthma are usually present for 8 to 10 years, and up to

30 years before CSS disease recognition.



2. VASCULITIC PHASE:• vasculitis of the small and medium vessels with vascular

and extravascular granulomas.

• The onset of the vasculitic phase is often heralded by

development of constitutional symptoms, including fever,

malaise, weight loss, and increased allergic or asthmatic

symptoms .



• Vasculitis tends to occur several years after the onset of

allergic manifestations

• In some cases it develops within months of, or

concomitant with, the onset of asthma.

• Typically affects multiple-organ systems.

• Manifestations in the lungs, heart, skin, and nervous

system are most commonFishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1224


3. THE EOSINOPHILIC PHASE:• Marked peripheral blood eosinophilia and eosinophilic

tissue infiltration, most commonly of lung, GIT, & skin.

RESPIRATORY MANIFESTATIONS:• Occur in the prodromal and eosinophilic phases of the

disease.

• Nearly all patients have asthma at some point in the illness.



RESPIRATORY MANIFESTATIONS: (contd)• Upper airway allergic disease, sinusitis, rhinitis, and

polyposis, is seen in 75 to 85 percent of patients.

• The asthma and upper-airway disease usually are

long-standing and often require steroid therapy

(systemic or inhaled) to maintain control of symptoms.

• In rare instances, recurrent respiratory infections leads to bronchiectasis.



RESPIRATORY MANIFESTATIONS: (contd)• A Loeffler’s-like syndrome with eosinophilic infiltration of

the lung parenchyma is seen in 38 to 40% of patients.

• These patients may develop dyspnea, cough, and

wheezing.

• PFT: obstructive ventilatory defect



SYSTEMIC MANIFESTATIONS:

Cardiac > CNS > renal > GIT

CARDIAC MANIFESTATIONS:• NOT present on initial presentation & occur during the

vasculitic phase.

• Major source of morbidity & mortality(in up to 50% of

cases).



• Progressive CHF occurs in 47% because of myocardial

infiltration by eosinophils or ischemic cardiomyopathy

due to necrotizing vasculitis of the coronary arteries.

• Coronary vasculitis is fatal up to 60% of time.

• Acute pericarditis(1/3rd cases), cardiac tamponade have

been reported.

• Constrictive pericarditis may develop over time.



NEUROLOGICAL MANIFESTATIONS:• Mono- or polyneuropathy (present in 69 to 75% of cases)

• CNS manifestations occur in approximately 2/3rd of patients & include:-

- cranial nerve impairment (especially optic neuritis), - seizure,- subarachnoid hemorrhage common causes of- cerebral infarction. patient death



DERMATOLOGICAL MANIFESTATIONS:• Seen in 2/3 rd cases

• They can manifest as: - Nonthrombocytopenic purpura, - Tender cutaneous or subcut. nodules (may ulcerate)- Urticaria, - Maculopapular rash, - Petechiae, ecchymoses, or - livedo reticularis



GI MANIFESTATIONS:• Present in 60% of cases & is the 4th leading cause of

death in CSS.

• They include - Eosinophilic gastroenteritis/vasculitis leading to diarrhea,

abdominal pain,

- Cholecystitis, Pancreatitis, Liver function abnormalities,- Intestinal obstruction, GI bleed & Bowel perforation may

occur.



RENAL MANIEFESTATIONS:• Renal insufficiency occurs in up to 50% of cases.

• Interstitial nephritis, FSGN(often with necrotizing features), hematuria & albuminuria are common.

• Severe hypertension may occur in 25-75 % of cases

& may be due to recurrent renal infarction.

• In contrast to WG, overt renal failure is not common.



OTHER MANIFESTATIONS:• Mild lymphadenopathy(in 30 to 40 percent),

• Rheumatological manifestations (migratory

polyarthralgias, myalgias, temporal arteritis),

• Urological disease (ureteral, urethral, prostatic),

• Ocular manifestations have also been described


Frequency of organ manifestation & clinical features of CSS

Rheum Dis Clin N Am 36 (2010) 527–543

Variants of CSSVasculitic phenotype Tissue disease phenotype

Frequency 40 % 60 %

ANCA Present (p ANCA) Absent

Predominant clinical feature Glomerular renal dsPeripheral neuropathyPurpura

Cardiac involvement(eosinophilic myocarditis)Fever

Predominant histopathological feature

Biopsy proven vasculitis Eosinophilic pneumonia

Rheum Dis Clin N Am 36 (2010) 527–543


INVESTIGATIONS• Fluctuating degree of peripheral blood eosinophilia

(20 to 90 percent of the WBC differential)

• S. Total IgE levels are elevated (range, 500-1000 U/ml)

& may parallel disease activity.

• normochromic, normocytic anemia.

• ESR- moderately elevated.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1225


INVESTIGATIONS: (contd)• 70-75% of patients have +ve pANCA.

• Pleural fluid, if present, reveals an acidotic

eosinophilic exudate with low glucose levels.

• Pleural biopsy shows chronic pleuritis with

eosinophilic infiltration.

• BAL reveals an increased percentage of eosinophilFishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1225


RADIOLOGY:• Transient, migratory nonlobar, nonsegmental, often

peripheral pulmonary infiltrates, with no regional

predilection.

• Nodular lesions, interstitial lung disease, and hilar

adenopathy are less common findings.

• The chest radiograph may occasionally be normal.



HRCT FINDINGS:• patchy peribronchial thickening,

• pulmonary artery enlargement,

• Irregular stellate configuration of some vessels,

• Areas of septal thickening,

• Scattered patchy parenchymal opacities with ground-

glass or consolidated appearance.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1225

Radiology

Transient migratory non lobar,Non segmental peripheral opacities

Scattered patchy opacities with Ground glass hazePatchy peribronchial thickening B/L pleural effusionPericardial effusion



• 18FDG/13N ammonia PET imaging may be useful to

identify cardiac involvement.

• The histopathological hallmarks depends on stage of

illness: -- Early lesions demonstrate eosinophilic infiltration of the

vessels and perivascular region.- Later lesions are characterized by necrotizing arteritis or

vessel obliteration and scarring.



• Open lung biopsy is the gold-standard site for tissue

biopsy.

• Transbronchial biopsy may reveal the diagnosis if there

is alveolar involvement, but is often non diagnostic..


High-power photomicrograph showing numerous eosinophils (arrows), each of which has a lobulated nucleus and cytoplasm that includes specific granules.


Microscopy


DIFFERENTIALS:• Polyarteritis nodosa, • Microscopic angiitis, • Wegner’s Granulomatosis,• CEP• ABPA • Idiopathic hypereosinophilic

syndrome,• Loeffler’s syndrome

• Asthma• Fungal or parasitic

infection, • Drug-induced vasculitis,• Sarcoidosis and • Hodgkin’s lymphoma



PROGNOSIS:• Patients in whom CSS goes untreated have a poor

prognosis

• Upto 50% die within 3 months of the onset of vasculitis.

• Early recognition and treatment are important.

• Corticosteroid treatment generally leads to dramatic

clinical improvement, with disease stabilization or cure.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1226


TREATMENT:• Prednisone,0.5 to 1.5 mg/kg/day (or 60 mg/day in adults)

for 6 to 12 weeks, to eliminate constitutional symptoms.

• Once the vasculitic phase is controlled, steroids may be

tapered with doses titrated to maintain disease control.

• Low-dose prednisone is often given every day or every

other day for up to 1 year.



TREATMENT : (contd)• Treatment with cytotoxic immunosuppressive agents

such as: azathioprine, cyclophosphamide, high-dose

methylprednisolone, or chlorambucil may prove effective.

• Should be considered in patients whose condition fails to

improve with steroid treatment or poor prognostic

features, including cardiac or GI involvement, renal

insufficiency or proteinuria greater than 1 g/day.



TREATMENT: (contd)• Cyclophosphamide (2 mg/kg/day orally or 0.6 g/m2 iv per

month) may be given concurrently with corticosteroids.

• IFN-α has led to improved pulmonary function tests,

• Plasma exchange may be a successful adjunct T/t.

• β-blockers should be avoided in CSS related HTn owing

to the risk of bronchospasm & CHF.



OUTCOME:• Long term overall remission can be achieved in 81 to 92

percent of patients.

• Relapses if occurs are usually within 1st year.

• Patients with severe disease when treated with

cyclophosphamide & corticosteroids have better survival

than those treated with corticosteroids alone.


Association between leukotriene receptor antagonists and Churg-Strauss syndrome

•The authors show that in two thirds of cases, LTRA therapy may be implicated in the pathogenesis of CSS.

•The association is much stronger than for long-acting beta- adrenergic agents or inhaled corticosteroids, which might be added as asthma worsens during the prodromal phase of CSS.

•The authors fail to identify a biologically plausible reason for the association, however, and many cases of CSS occur in the absence of LTRA therapy.

Bibby S, Healy B, Steele R, et al: Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: An analysis of the FDA AERS database. Thorax 2010; 65(2):132-138.

IDIOPATHIC

HYPEREOSINOPHILIC

SYNDROME

IDIOPATHIC HYPEREOSINOPHILIC SYNDROME

• Several names-including: Eosinophilic leukemia, Loeffler’s fibroplastic endocarditis, Disseminated eosinophilic cardiovascular disease.

• In 1975, Chusid and colleagues revised the definition of

IHS to include only cases in which no other underlying

cause of hypereosinophilia could be found.



CLINICAL FEATURES:• Clinically heterogeneous syndrome with a wide range of

disease severity.

• Predominantly affects males between 20 to 50 yrs of age

• Clinical features varies from mild limited form of disease

with minimal involvement of non critical organ to life

threatening multi organ dysfunction.



CLINICAL FEATURES: (contd)• Often nonspecific & include:

weakness, fatigue, low-grade fevers, myalgias, cough,

angioedema, rash, retinal lesions, and dyspnea.

• virtually every organ system can be involved.

• Cough is predominantly nocturnal ,either nonproductive or productive of small quantities of non-purulent sputum.



CLINICAL FEATURES:• Wheezing and dyspnea are also common, without

evidence of airflow obstruction on spirometry

• Pulmonary hypertension, ARDS, and pleural effusions

(which may be due to CHF) have been reported.

• Chest x ray:

Transient focal or diffuse pulmonary infiltrates (with no

predilection for any particular distribution )Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1227


CLINICAL FEATURES: (contd)

*The three principal clinical features defining IHS are:

(1) persistent blood eosinophilia greater than 1500/μl

for more than 6 months;

(2) symptoms and signs of end-organ dysfunction; and

(3) no other identifiable underlying cause of

eosinophilia.

• Histopathological examination reveals intense interstitial

infilteration with eosinophils.*Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). Jan 1975;54(1):1-27.


CARDIAC MANIFESTATIONS:• Occurs in most patients with IHS & is the major cause of

morbidity and mortality.

• Includes:- Progressive CHF due to eosinophilic myocarditis &

endocarditis- intracardiac thrombi- endocardial fibrosis.



NEUROLOGICAL MANIFESTATIONS:• Encephalopathy with neuropsychiatric dysfunction,• Memory loss, • Gait disturbances with or without signs of upper motor

neuron injury, • Visual changes,• Sequelae of thromboembolic events, like hemiparesis. • Peripheral neuropathy with sensory and/or motor axonal

loss (no vasculitic or eosinophilic infiltration) is

extremely common in IHS.



OTHER MANIFESTATIONS:

- Venous and arterial thromboembolism, - Anemia,- Thrombocytopenia, - Elevated vitamin B12 levels, - Hepatosplenomegaly,- Lymphadenopathy

• The bone marrow is universally affected with a striking

eosinophilia (up to 25 to 75 percent of the differential).Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1228

Clinical features of HES


• Organ damage in IHS is believed to be due both to

eosinophilic infiltration of tissues and to tissue injury

caused by thromboembolic events.

• Eosinophils probably contribute to tissue damage via

antibody mediated cytotoxicity.

• BAL eosinophilia is absent in patients lacking pulmonary

manifestations of the disease.



LABORATORY FINDINGS:• Elevated serum total IgE (25 to 38 percent)• Hypergammaglobulinemia• Circulating immune complexes (32 to 50 percent)• ESR above 15 mm/h (68 percent)• Elevated serum B12 and leukocyte alkaline phosphatase

levels are also noted• Fungal and parasitic serologies, as well as aspirates of

body fluids for ova and parasites, are negative.



Major pathogenetic and clinical variants:• Patients with clonal abnormalities in eosinophils

• Patients with features of myeloproliferative disorder

and chromosomal aberrations leading to abnormal

constitutive production of tyrosine kinases

• Patients with dysregulation of T lymphocytes with

overproduction of IL-5, a cytokine important for

eosinophil growth, differentiation, and chemotaxis.Fishman’s pulmonary diseases & disorders. 4th edition. Kristina crothers, carolyn rochester. The Eosinophilic Pneumonias; Vol1: 72: pg 1228


*DIAGNOSTIC CRITERIA:• A sustained absolute eosinophil count (AEC) greater

than >1500/µl is present, which persists for >6 months.• No identifiable etiology for eosinophilia is present.• Patients must have signs and symptoms of multi-organ

involvement.

• Peripheral leukocyte count is typically elevated to above

10,000 (typical range, 10,000 to 30,000), with a

preponderance of eosinophils (up to 70 percent).

*Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). Jan 1975;54(1):1-27.

Redefining HES

J ALLERGY CLIN IMMUNOL JULY 2010


DIFFERENTIAL DIAGNOSIS:• Parasitic infection• Acute Eosinophilic Leukemia• CSS• Episodic angioedema with eosinophilia• Tuberculous or fungal infection • Allergic or autoimmune disease• Acute or CEPs, TPE, and other lymphoproliferative

disorders.



TREATMENT:• Currently, there are no recommendations for treating

asymptomatic patients with hypereosinophilic syndrome,

• Such patients are closely monitored with serum troponin

level every 3-6 months, and ECHO and pulmonary

function tests every 6-12 months.

• Glucocorticoids are the first line therapy in all patients

without FIP1L1/PDGFRAmutationKlion AD, Bochner BS, Gleich GJ, et al, and The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. Jun 2006;117(6):1292-302.


TREATMENT: (contd)• Hydroxyurea (0.5 to 1.5 g per day) may be added if there

is evidence of further disease progression, with the aim

of reducing the TLC to the range of 5000 to 10,000.

• A high dose (400 mg) of imatinib is the t/t of choice, if first & second line drug fails.

• For those with FIP1L1/PDGFRA mutation, imatinib is the drug of choice with a very good response rate that approaches 100% in various studies.

Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med. Aug 1978;89(2):167-72.


TREATMENT: (contd)• Vincristine may be used as a chemotherapeutic inducing

agent in patients with extremely high TLC.

• Etoposide & chlorambucil are effective alternative for cases refractory to standard treatment with steroids.

• Cyclosporine may also be of benefit in controlling the disease, especially in combination with corticosteroids.

Klion AD, Bochner BS, Gleich GJ, et al, and The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol. Jun 2006;117(6):1292-302


• IFN- α should be tried as a second-line agent among patients with IHS who fail to respond to corticosteroid treatment.

• A humanized anti–IL-5 monoclonal antibody (eg, mepolizumab) and an anti-CD52 antibody (alemtuzumab) have been shown to control symptoms as well as eosinophilia.

Schwartz LB, Sheikh J, Singh A. Current strategies in the management of hypereosinophilic syndrome, including mepolizumab. Curr Med Res Opin. Aug 2010;26(8):1933-46.

EOSINOPHILIA> 5% or AEC > 500/mm3

RPT COUNTS

STOOL EXAM &X RAY

SP ANTIBODY FOR FILARIA,ASCARIS,ANCYLOSTOMA

STRONGYLOIDES,ASCARIS,SCHISTOSTOMA,ANCYLOSTOMA

PFTOBSTRUCTIVE

EXTRA PULM INVOLVEMENT

CSS

PULM ONLY

X RAY NORMAL &IgE < 1000

ASTHMA

X RAY ABN &IgE > 1000

ABPA

RESTRICTIVE

BAL

< 20 % EOSINOPHIL

ILDDRUG REACTION

> 20 % EOSINOPHIL

BLOOD EOSINOPHILS

HIGH>5000

MODERATE1500-5000 mm3

LOW/NORMAL500-1500 mm3

AEP CEPLOEFFLER SYNDROME

HES

Allen JN, Davis WB: Eosinophilic lung diseases. Am J Respir Crit CareMed 150:1423–1438, 1994

Approach

D.M. Savani, O.P. Sharma / Clin Chest Med 23 (2002) 377–396

IgE levels in PIE

D.M. Savani, O.P. Sharma / Clin Chest Med 23 (2002) 377–396

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Eosinophillic lung diseases

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